Thin films and coatings that sustain the release of DNA from surfaces are playing an important role in the development of localized approaches to gene therapy. For example, polymer-coated intravascular stents have been used to localize the delivery of DNA to the vascular wall and could lead to innovative gene-based treatments for vascular diseases or related conditions. Likewise, plasmid-eluting polymer matrices have been applied to the localized delivery of DNA to cells in the context of tissue engineering. The integration of design elements and new chemical functionalities that provide for the erosion of polyelectrolyte films under physiological conditions have been described for use in certain therapeutic areas. Several groups have reported the enzymatic degradation of multilayered films fabricated from naturally occurring polyelectrolytes such as chitosan/dextran sulfate, DNA, or hyaluronic acid and chitosan.
Intravascular stents have previously demonstrated potential as platforms for the localized delivery of DNA. This past work has focused largely on the encapsulation of plasmid DNA in thin films of degradable polymer (I. Fishbein, et al., Site specific gene delivery in the cardiovascular system. J Control Release 2005, 109, 37-48; B. D. Klugherz, et al., Gene delivery from a DNA controlled-release stent in porcine coronary arteries. Nat Biotechnol 2000, 18, 1181-4; I. Perlstein, et al., DNA delivery from an intravascular stent with a denatured collagen-polylactic-polyglycolic acid-controlled release coating: mechanisms of enhanced transfection. Gene Ther 2003, 10, 1420-8; A. Takahashi, et al., Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent. Gene Ther 2003, 10, 1471-8; D. H. Walter, et al., Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: an alternative strategy for inhibition of restenosis. Circulation 2004, 110, 36-45.) or the tethering of viruses to collagen-coated stents (B. D. Klugherz, et al., Gene delivery to pig coronary arteries from stents carrying antibody-tethered adenovirus. Hum Gene Ther 2002, 13, 443-54) or bare metal stents (I. Fishbein, et al., Bisphosphonate-mediated gene vector delivery from the metal surfaces of stents. Proc Natl Acad Sci USA 2006, 103, 159-164).
In the long term, methods for non-viral gene delivery have the potential to be safer than methods based on the use of viruses. However, past studies on stent-mediated delivery of plasmid DNA have made use of relatively thick (micrometer-scale) films using polymers that have been observed to lead to inflammatory responses in vivo. In addition, conventional methods for the bulk encapsulation of DNA involve the use of organic solvents, and these methods provide limited control over DNA loading and the spatial distribution of encapsulated DNA. The development of ultrathin films that combine the ability to localize DNA at a surface with the ability to control release profiles and promote subsequent internalization would constitute a significant advance and make possible new approaches to localized gene delivery.
Although various degradable polymer matrices have been described that are capable of sustaining the release of encapsulated DNA, general methods for the direct, localized, and sequential delivery of nucleic acid from thin films and surfaces do not yet exist. Such direct transfection materials and methods would be particularly advantageous in medical applications including, but not limited to, localized gene therapy, the growth or regeneration of complex tissues and other therapeutic uses such as inhibiting and/or ameliorating the inflammation that accompanies the implantation of medical devices such as vascular stents, prosthesis and the like.